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1.
PLoS Comput Biol ; 16(9): e1008165, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32941457

RESUMO

Combining information from multiple sources is a fundamental operation performed by networks of neurons in the brain, whose general principles are still largely unknown. Experimental evidence suggests that combination of inputs in cortex relies on nonlinear summation. Such nonlinearities are thought to be fundamental to perform complex computations. However, these non-linearities are inconsistent with the balanced-state model, one of the most popular models of cortical dynamics, which predicts networks have a linear response. This linearity is obtained in the limit of very large recurrent coupling strength. We investigate the stationary response of networks of spiking neurons as a function of coupling strength. We show that, while a linear transfer function emerges at strong coupling, nonlinearities are prominent at finite coupling, both at response onset and close to saturation. We derive a general framework to classify nonlinear responses in these networks and discuss which of them can be captured by rate models. This framework could help to understand the diversity of non-linearities observed in cortical networks.


Assuntos
Potenciais de Ação/fisiologia , Modelos Neurológicos , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Animais , Encéfalo/citologia , Encéfalo/fisiologia , Biologia Computacional , Haplorrinos , Camundongos , Dinâmica não Linear
2.
Korean J Parasitol ; 58(4): 461-466, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32871641

RESUMO

Toxoplasma gondii is an obligate intracellular protozoan parasite that can invade various organs in the host body, including the central nervous system. Chronic intracranial T. gondii is known to be associated with neuroprotection against neurodegenerative diseases through interaction with host brain cells in various ways. The present study investigated the neuroprotective effects of chronic T. gondii infection in mice with cerebral ischemia experimentally produced by middle cerebral artery occlusion (MCAO) surgery. The neurobehavioral effects of cerebral ischemia were assessed by measurement of Garcia score and Rotarod behavior tests. The volume of brain ischemia was measured by triphenyltetrazolium chloride staining. The expression levels of related genes and proteins were determined. After cerebral ischemia, corrected infarction volume was significantly reduced in T. gondii infected mice, and their neurobehavioral function was significantly better than that of the uninfection control group. Chronic T. gondii infection induced the expression of hypoxia-inducible factor 1-alpha (HIF-1α) in the brain before MCAO. T. gondii infection also increased the expression of vascular endothelial growth factor after the cerebral ischemia. It is suggested that chronic intracerebral infection of T. gondii may be a potential preconditioning strategy to reduce neural deficits associated with cerebral ischemia and induce brain ischemic tolerance through the regulation of HIF-1α expression.


Assuntos
Isquemia Encefálica/prevenção & controle , Encéfalo/parasitologia , Interações Hospedeiro-Parasita , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neuroproteção , Toxoplasma/fisiologia , Toxoplasmose/fisiopatologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Encéfalo/patologia , Isquemia Encefálica/parasitologia , Isquemia Encefálica/patologia , Modelos Animais de Doenças , Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Camundongos Endogâmicos ICR , Tamanho do Órgão , Toxoplasmose/metabolismo , Toxoplasmose/patologia
3.
Nat Commun ; 11(1): 4363, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868797

RESUMO

A specialized neurogenic niche along the ventricles accumulates millions of progenitor cells in the developing brain. After mitosis, fate-committed daughter cells delaminate from this germinative zone. Considering the high number of cell divisions and delaminations taking place during embryonic development, brain malformations caused by ectopic proliferation of misplaced progenitor cells are relatively rare. Here, we report that a process we term developmental anoikis distinguishes the pathological detachment of progenitor cells from the normal delamination of daughter neuroblasts in the developing mouse neocortex. We identify the endocannabinoid-metabolizing enzyme abhydrolase domain containing 4 (ABHD4) as an essential mediator for the elimination of pathologically detached cells. Consequently, rapid ABHD4 downregulation is necessary for delaminated daughter neuroblasts to escape from anoikis. Moreover, ABHD4 is required for fetal alcohol-induced apoptosis, but not for the well-established form of developmentally controlled programmed cell death. These results suggest that ABHD4-mediated developmental anoikis specifically protects the embryonic brain from the consequences of sporadic delamination errors and teratogenic insults.


Assuntos
Anoikis , Lisofosfolipase , Neocórtex/embriologia , Animais , Encéfalo/citologia , Encéfalo/embriologia , Diferenciação Celular , Transtornos do Espectro Alcoólico Fetal/etiologia , Transtornos do Espectro Alcoólico Fetal/metabolismo , Expressão Gênica , Células HEK293 , Humanos , Lisofosfolipase/genética , Lisofosfolipase/metabolismo , Camundongos , Neocórtex/citologia , Células-Tronco Neurais , Filogenia
4.
PLoS Comput Biol ; 16(8): e1008120, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32804935

RESUMO

Complexity of cell-type composition has created much skepticism surrounding the interpretation of bulk tissue transcriptomic studies. Recent studies have shown that deconvolution algorithms can be applied to computationally estimate cell-type proportions from gene expression data of bulk blood samples, but their performance when applied to brain tissue is unclear. Here, we have generated an immunohistochemistry (IHC) dataset for five major cell-types from brain tissue of 70 individuals, who also have bulk cortical gene expression data. With the IHC data as the benchmark, this resource enables quantitative assessment of deconvolution algorithms for brain tissue. We apply existing deconvolution algorithms to brain tissue by using marker sets derived from human brain single cell and cell-sorted RNA-seq data. We show that these algorithms can indeed produce informative estimates of constituent cell-type proportions. In fact, neuronal subpopulations can also be estimated from bulk brain tissue samples. Further, we show that including the cell-type proportion estimates as confounding factors is important for reducing false associations between Alzheimer's disease phenotypes and gene expression. Lastly, we demonstrate that using more accurate marker sets can substantially improve statistical power in detecting cell-type specific expression quantitative trait loci (eQTLs).


Assuntos
Algoritmos , Encéfalo , Perfilação da Expressão Gênica/métodos , Análise de Sequência de RNA/métodos , Transcriptoma/genética , Encéfalo/citologia , Encéfalo/metabolismo , Biologia Computacional , Humanos , Imuno-Histoquímica , Especificidade de Órgãos/genética , Fenótipo , Locos de Características Quantitativas/genética , Análise de Célula Única
5.
Science ; 369(6503): 530-537, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32732419

RESUMO

Microglia, immune cells of the central nervous system (CNS), are important for tissue development and maintenance and are implicated in CNS disease, but we lack understanding of human fetal microglia development. Single-cell gene expression and bulk chromatin profiles of microglia at 9 to 18 gestational weeks (GWs) of human fetal development were generated. Microglia were heterogeneous at all studied GWs. Microglia start to mature during this developmental period and increasingly resemble adult microglia with CNS-surveilling properties. Chromatin accessibility increases during development with associated transcriptional networks reflective of adult microglia. Thus, during early fetal development, microglia progress toward a more mature, immune-sensing competent phenotype, and this might render the developing human CNS vulnerable to environmental perturbations during early pregnancy.


Assuntos
Encéfalo/embriologia , Desenvolvimento Embrionário/imunologia , Feto/imunologia , Microglia/imunologia , Fagocitose/imunologia , Encéfalo/citologia , Separação Celular , Células Cultivadas , Desenvolvimento Embrionário/genética , Redes Reguladoras de Genes , Humanos , Fagocitose/genética , Transcriptoma
6.
Nat Commun ; 11(1): 4275, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32848155

RESUMO

New neurons are generated in adult mammals. Adult hippocampal neurogenesis is considered to play an important role in cognition and mental health. The number and properties of newly born neurons are regulatable by a broad range of physiological and pathological conditions. To begin to understand the underlying cellular mechanisms and functional relevance of adult neurogenesis, many studies rely on quantification of adult-born neurons. However, lack of standardized methods to quantify new neurons is impeding research reproducibility across laboratories. Here, we review the importance of stereology, and propose why and how it should be applied to the study of adult neurogenesis.


Assuntos
Encéfalo/citologia , Encéfalo/fisiologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Adulto , Células-Tronco Adultas/citologia , Células-Tronco Adultas/fisiologia , Animais , Giro Denteado/citologia , Giro Denteado/fisiologia , Humanos , Modelos Neurológicos , Plasticidade Neuronal
7.
J Pharmacol Sci ; 144(2): 76-82, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32736867

RESUMO

Astrocytes, comprising the primary glial-cell type, are involved in the formation and maturation of synapses, and thus contribute to sustainable synaptic transmission between neurons. Given that the animals in higher phylogenetic tree have brains with a higher density of glial cells with respect to neurons, there is a possibility that the relative astrocytic density directly influences synaptic transmission. However, the notion has not been tested thoroughly. Here we addressed it, by using a primary culture preparation where single hippocampal neurons are surrounded by a variable but a countable number of cortical astrocytes in dot-patterned microislands, and recording synaptic transmission by patch-clamp electrophysiology. Neurons with a higher astrocytic density showed a higher amplitude of the evoked excitatory postsynaptic current than that of neurons with a lower astrocytic density. The size of the readily releasable pool of synaptic vesicles per neuron was significantly larger. The frequency of spontaneous synaptic transmission was higher, but the amplitude was unchanged. The number of morphologically identified glutamatergic synapses was comparable, but the percentage of functional ones was increased, indicating a lower ratio of presynaptically silent synapses. Taken together, the higher astrocytic density enhanced excitatory synaptic transmission by increasing the fraction of functional synapses through presynaptic un-silencing.


Assuntos
Astrócitos/fisiologia , Encéfalo/citologia , Neurônios/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , Animais , Astrócitos/patologia , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores , Feminino , Camundongos Endogâmicos ICR , Neurônios/patologia , Filogenia , Gravidez
9.
PLoS Biol ; 18(8): e3000548, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32745077

RESUMO

Sleep is vital for survival. Yet under environmentally challenging conditions, such as starvation, animals suppress their need for sleep. Interestingly, starvation-induced sleep loss does not evoke a subsequent sleep rebound. Little is known about how starvation-induced sleep deprivation differs from other types of sleep loss, or why some sleep functions become dispensable during starvation. Here, we demonstrate that down-regulation of the secreted cytokine unpaired 2 (upd2) in Drosophila flies may mimic a starved-like state. We used a genetic knockdown strategy to investigate the consequences of upd2 on visual attention and sleep in otherwise well-fed flies, thereby sidestepping the negative side effects of undernourishment. We find that knockdown of upd2 in the fat body (FB) is sufficient to suppress sleep and promote feeding-related behaviors while also improving selective visual attention. Furthermore, we show that this peripheral signal is integrated in the fly brain via insulin-expressing cells. Together, these findings identify a role for peripheral tissue-to-brain interactions in the simultaneous regulation of sleep quality and attention, to potentially promote adaptive behaviors necessary for survival in hungry animals.


Assuntos
Atenção/fisiologia , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Comportamento Alimentar/fisiologia , Inanição/genética , Percepção Visual/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Proteínas de Drosophila/deficiência , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Corpo Adiposo/metabolismo , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Insulina/genética , Insulina/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Transdução de Sinais , Sono/fisiologia , Privação do Sono/genética , Privação do Sono/metabolismo , Inanição/metabolismo
10.
J Vis Exp ; (160)2020 06 23.
Artigo em Inglês | MEDLINE | ID: mdl-32658196

RESUMO

Microglia and central nervous system (CNS)-infiltrating macrophages, collectively called CNS mononuclear phagocytes (CNS-MPs), play central roles in neurological diseases including neurodegeneration and stroke. CNS-MPs are involved in phagocytic clearance of pathological proteins, debris and neuronal synapses, each with distinct underlying molecular pathways. Characterizing these phagocytic properties can provide a functional readout that compliments molecular profiling of microglia using traditional flow cytometry, transcriptomics and proteomics approaches. Phagocytic profiling of microglia has relied on microscopic visualization and in vitro cultures of mouse neonatal microglia. The former approach suffers from limited sampling while the latter approach is inherently poorly reflective of the true in vivo state of adult CNS-MPs. This paper describes optimized protocols to phenotype phagocytic properties of acutely-isolated mouse CNS-MPs by flow cytometry. CNS-MPs are acutely isolated from adult mouse brain using mechanical dissociation followed by density gradient centrifugation, incubated with fluorescent microspheres or fluorescent Aß fibrils, washed, and then labeled with panels of antibodies against surface markers (CD11b, CD45). Using this approach, it is possible to compare phagocytic properties of brain-resident microglia with CNS-infiltrating macrophages and then assess the effect of aging and disease pathology on these phagocytic phenotypes. This rapid method also holds potential to functionally phenotype acutely-isolated human CNS-MPs from post-mortem or surgical brain specimens. Additionally, specific mechanisms of phagocytosis by CNS-MP subsets can be investigated by inhibiting select phagocytic pathways.


Assuntos
Encéfalo/citologia , Citometria de Fluxo/métodos , Macrófagos/citologia , Microglia/imunologia , Fagocitose , Adulto , Antígeno CD11b/metabolismo , Humanos , Antígenos Comuns de Leucócito/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo
11.
Proc Natl Acad Sci U S A ; 117(31): 18661-18669, 2020 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-32675242

RESUMO

Huntington's disease (HD) is a progressive incurable neurodegenerative disorder characterized by motor and neuropsychiatric symptoms. It is caused by expansion of a cytosine-adenine-guanine triplet in the N-terminal domain of exon 1 in the huntingtin (HTT) gene that codes for an expanded polyglutamine stretch in the protein product which becomes aggregation prone. The mutant Htt (mHtt) aggregates are associated with components of the ubiquitin-proteasome system, suggesting that mHtt is marked for proteasomal degradation and that, for reasons still debated, are not properly degraded. We used a novel HD rat model, proteomic analysis, and long-term live neuronal imaging to characterize the effects of ubiquitination on aggregation of mHtt and subsequent cellular responses. We identified two lysine residues, 6 and 9, in the first exon of mHtt that are specifically ubiquitinated in striatal and cortical brain tissues of mHtt-transgenic animals. Expression of mHtt exon 1 lacking these ubiquitination sites in cortical neurons and cultured cells was found to slow aggregate appearance rates and reduce their size but at the same time increase the number of much smaller and less visible ones. Importantly, expression of this form of mHtt was associated with elevated death rates. Proteomic analysis indicated that cellular reactions to mHtt expression were weaker in cells expressing the lysineless protein, possibly implying a reduced capacity to cope with the proteotoxic stress. Taken together, the findings suggest a novel role for ubiquitination-attenuation of the pathogenic effect of mHtt.


Assuntos
Proteína Huntingtina , Doença de Huntington , Ubiquitinação/fisiologia , Animais , Encéfalo/citologia , Encéfalo/metabolismo , Morte Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/química , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Lisina/química , Lisina/metabolismo , Neurônios/metabolismo , Complexo de Endopeptidases do Proteassoma , Agregação Patológica de Proteínas/metabolismo , Ratos , Ratos Transgênicos
12.
PLoS One ; 15(7): e0236113, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687511

RESUMO

Loss of function mutations in the gene encoding the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to severe neurodevelopmental defects in humans associated with a specific thyroid hormone phenotype manifesting high serum 3,5,3'-triiodothyronine (T3) and low thyroxine (T4) levels. Patients present a paradoxical state of peripheral hyperthyroidism and brain hypothyroidism, this last one most likely arising from impaired thyroid hormone transport across the brain barriers. The administration of thyroid hormones by delivery pathways that bypass the brain barriers, such as the intranasal delivery route, offers the possibility to improve the neurological defects of MCT8-deficient patients. In this study, the thyroid hormones T4 and T3 were administrated intranasally in different mouse models of MCT8 deficiency. We have found that, under the present formulation, intranasal administration of thyroid hormones does not increase the content of thyroid hormones in the brain and further raises the peripheral thyroid hormone levels. Our data suggests intranasal delivery of thyroid hormones is not a suitable therapeutic strategy for MCT8 deficiency, although alternative formulations could be considered in the future to improve the nose-to-brain transport.


Assuntos
Transportadores de Ácidos Monocarboxílicos/deficiência , Simportadores/deficiência , Hormônios Tireóideos/administração & dosagem , Hormônios Tireóideos/farmacologia , Administração Intranasal , Animais , Encéfalo/citologia , Camundongos , Transportadores de Ácidos Monocarboxílicos/genética , Mutação , Transdução de Sinais/efeitos dos fármacos , Simportadores/genética , Hormônios Tireóideos/sangue
13.
Nat Commun ; 11(1): 3791, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32728089

RESUMO

Brain organoids are promising tools for disease modeling and drug development. For proper neuronal network formation excitatory and inhibitory neurons as well as glia need to co-develop. Here, we report the directed self-organization of human induced pluripotent stem cells in a collagen hydrogel towards a highly interconnected neuronal network at a macroscale tissue format. Bioengineered Neuronal Organoids (BENOs) comprise interconnected excitatory and inhibitory neurons with supportive astrocytes and oligodendrocytes. Giant depolarizing potential (GDP)-like events observed in early BENO cultures mimic early network activity of the fetal brain. The observed GABA polarity switch and reduced GDPs in >40 day BENO indicate progressive neuronal network maturation. BENOs demonstrate expedited complex network burst development after two months and evidence for long-term potentiation. The similarity of structural and functional properties to the fetal brain may allow for the application of BENOs in studies of neuronal plasticity and modeling of disease.


Assuntos
Encéfalo/citologia , Neurogênese , Plasticidade Neuronal/fisiologia , Organoides/fisiologia , Engenharia Tecidual/métodos , Potenciais de Ação/fisiologia , Encéfalo/crescimento & desenvolvimento , Técnicas de Cultura de Células , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurônios/fisiologia , Ácido gama-Aminobutírico/metabolismo
14.
Med Sci (Paris) ; 36(6-7): 581-591, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32614308

RESUMO

Following partial or total loss of peripheral vestibular inputs, a phenomenon called central vestibular compensation takes place in the hours and days following the injury. This neuroplasticity process involves a mosaic of profound rearrangements within the brain stem vestibular nuclei. Among them, the setting of a new neuronal network is maybe the most original and unexpected, as it involves an adult reactive neurogenesis in a brain area not reported as neurogenic so far. Both the survival and functionality of this newly generated neuronal network will depend on its integration to pre-existing networks in the deafferented structure. Far from being aberrant, this new structural organization allows the use of inputs from other sensory modalities (vision and proprioception) to promote the restoration of the posture and equilibrium. We choose here to detail this model, which does not belong to the traditional niches of adult neurogenesis, but it is the best example so far of the reparative role of the adult neurogenesis. Not only it represents an original neuroplasticity mechanism, interesting for basic neuroscience, but it also opens new medical perspectives for the development of therapeutic approaches to alleviate vestibular disorders.


Assuntos
Encéfalo/citologia , Neurogênese/fisiologia , Neurônios/fisiologia , Postura/fisiologia , Doenças Vestibulares/reabilitação , Núcleos Vestibulares/lesões , Adulto , Células-Tronco Adultas/citologia , Células-Tronco Adultas/fisiologia , Animais , Encéfalo/fisiologia , Humanos , Células-Tronco Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Doenças Vestibulares/fisiopatologia , Núcleos Vestibulares/patologia , Núcleos Vestibulares/fisiologia , Vestíbulo do Labirinto/lesões , Vestíbulo do Labirinto/patologia , Vestíbulo do Labirinto/fisiologia
16.
Nat Commun ; 11(1): 3278, 2020 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32606311

RESUMO

On-implant spike sorting methods employ static feature extraction/selection techniques to minimize the hardware cost. Here we propose a novel framework for real-time spike sorting based on dynamic selection of features. We select salient features that maximize the geometric-mean of between-class distances as well as the associated homogeneity index effectively to best discriminate spikes for classification. Wave-shape classification is performed based on a multi-label window discrimination approach. An external module calculates the salient features and discrimination windows through optimizing a replica of the on-implant operation, and then configures the on-implant spike sorter for real-time online operation. Hardware implementation of the on-implant online spike sorter for 512 channels of concurrent extra-cellular neural signals is reported, with an average classification accuracy of ~88%. Compared with other similar methods, our method shows reduction in classification error by a factor of ~2, and also reduction in the required memory space by a factor of ~5.


Assuntos
Potenciais de Ação/fisiologia , Algoritmos , Encéfalo/fisiologia , Modelos Neurológicos , Neurônios/fisiologia , Processamento de Sinais Assistido por Computador/instrumentação , Encéfalo/citologia , Eletrofisiologia/instrumentação , Eletrofisiologia/métodos , Humanos , Neuroestimuladores Implantáveis
17.
Gene ; 758: 144975, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32707302

RESUMO

Dip2C is highly expressed in brain and many other tissues but its biological functions are still not clear. Genes regulated by Dip2C in brain have never been studied. The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated protein (Cas) systems, adaptive immune systems of bacteria and archaea, have been recently developed and broadly used in genome editing. Here, we describe targeted gene deletions of Dip2c gene in mice via CRISPR/Cas9 system and study of brain transcriptome under Dip2C regulation. The CRISPR/Cas9 system effectively generated targeted deletions of Dip2c by pronuclei injection of plasmids that express Cas9 protein and two sgRNAs. We achieved targeted large fragment deletion with efficiencies at 14.3% (1/7), 66.7% (2/3) and 20% (1/5) respectively in 3 independent experiments, averaging 26.7%. The large deletion DNA segments are 160.4 kb (Dip2CΔ160kb), spanning from end of exon 4 to mid of exon 38. A mouse with two base pair deletion was generated from a single sgRNA targeting in exon 4 (Dip2cΔ2bp) by non-homologous end joining (NHEJ). Loss of gene expression for Dip2c mRNA was confirmed by quantitative real-time PCR (qPCR). Dip2C-regulated genes and pathways in brain were investigated through RNAseq of Dip2cΔ2bp. In total, 838 genes were found differentially regulated, with 252 up and 586 down. Gene ontology (GO) analysis indicated that DEGs in brain are enriched in neurological functions including 'memory', 'neuropeptide signaling pathway', and 'response to amphetamine' while KEGG analysis shows that 'neuroactive ligand-receptor interaction pathway' is the most significantly enriched. DEGs Grid2ip, Grin2a, Grin2c, Grm4, Gabbr2, Gabra5, Gabre, Gabrq, Gabra6 and Gabrr2 are among the highly regulated genes by Dip2C. Results confirm Dip2C may play important roles in brain development and function.


Assuntos
Encéfalo/metabolismo , Regulação da Expressão Gênica/genética , Proteínas de Neoplasias/genética , Transcriptoma/genética , Animais , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Sistemas CRISPR-Cas , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Feminino , Deleção de Genes , Edição de Genes/métodos , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Knockout , RNA Guia/genética
18.
Nat Commun ; 11(1): 3625, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681001

RESUMO

Recurrently connected networks of spiking neurons underlie the astounding information processing capabilities of the brain. Yet in spite of extensive research, how they can learn through synaptic plasticity to carry out complex network computations remains unclear. We argue that two pieces of this puzzle were provided by experimental data from neuroscience. A mathematical result tells us how these pieces need to be combined to enable biologically plausible online network learning through gradient descent, in particular deep reinforcement learning. This learning method-called e-prop-approaches the performance of backpropagation through time (BPTT), the best-known method for training recurrent neural networks in machine learning. In addition, it suggests a method for powerful on-chip learning in energy-efficient spike-based hardware for artificial intelligence.


Assuntos
Encéfalo/fisiologia , Modelos Neurológicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Recompensa , Potenciais de Ação/fisiologia , Animais , Encéfalo/citologia , Aprendizado Profundo , Humanos , Camundongos , Plasticidade Neuronal/fisiologia
19.
Nat Commun ; 11(1): 3687, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703941

RESUMO

Microglia, resident immune cells of the CNS, are thought to defend against infections. Toxoplasma gondii is an opportunistic infection that can cause severe neurological disease. Here we report that during T. gondii infection a strong NF-κB and inflammatory cytokine transcriptional signature is overrepresented in blood-derived macrophages versus microglia. Interestingly, IL-1α is enriched in microglia and IL-1ß in macrophages. We find that mice lacking IL-1R1 or IL-1α, but not IL-1ß, have impaired parasite control and immune cell infiltration within the brain. Further, we show that microglia, not peripheral myeloid cells, release IL-1α ex vivo. Finally, we show that ex vivo IL-1α release is gasdermin-D dependent, and that gasdermin-D and caspase-1/11 deficient mice show deficits in brain inflammation and parasite control. These results demonstrate that microglia and macrophages are differently equipped to propagate inflammation, and that in chronic T. gondii infection, microglia can release the alarmin IL-1α, promoting neuroinflammation and parasite control.


Assuntos
Interleucina-1alfa/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Microglia/imunologia , Proteínas de Ligação a Fosfato/metabolismo , Toxoplasma/imunologia , Toxoplasmose Cerebral/imunologia , Animais , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/parasitologia , Encéfalo/patologia , Células Cultivadas , Doença Crônica , Modelos Animais de Doenças , Humanos , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Proteínas de Ligação a Fosfato/genética , Proteínas de Ligação a Fosfato/imunologia , Toxoplasma/isolamento & purificação , Toxoplasmose Cerebral/sangue , Toxoplasmose Cerebral/parasitologia , Toxoplasmose Cerebral/patologia
20.
PLoS One ; 15(7): e0234792, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614850

RESUMO

The Myo/Nog cell lineage was discovered in the chick embryo and is also present in adult mammalian tissues. The cells are named for their expression of mRNA for the skeletal muscle specific transcription factor MyoD and bone morphogenetic protein inhibitor Noggin. A third marker for Myo/Nog cells is the cell surface molecule recognized by the G8 monoclonal antibody (mAb). G8 has been used to detect, track, isolate and kill Myo/Nog cells. In this study, we screened a membrane proteome array for the target of the G8 mAb. The array consisted of >5,000 molecules, each synthesized in their native confirmation with appropriate post-translational modifications in a single clone of HEK-293T cells. G8 mAb binding to the clone expressing brain-specific angiogenesis inhibitor 1 (BAI1) was detected by flow cytometry, re-verified by sequencing and validated by transfection with the plasmid construct for BAI1. Further validation of the G8 target was provided by enzyme-linked immunosorbent assay. The G8 epitope was identified by screening a high-throughput, site directed mutagenesis library designed to cover 95-100% of the 954 amino acids of the extracellular domain of the BAI1 protein. The G8 mAb binds within the third thrombospondin repeat of the extracellular domain of human BAI1. Immunofluorescence localization experiments revealed that G8 and a commercially available BAI1 mAb co-localize to the subpopulation of Myo/Nog cells in the skin, eyes and brain. Expression of the multi-functional BAI1 protein in Myo/Nog cells introduces new possibilities for the roles of Myo/Nog cells in normal and diseased tissues.


Assuntos
Proteínas Angiogênicas/biossíntese , Miofibroblastos/metabolismo , Receptores Acoplados a Proteínas-G/biossíntese , Substituição de Aminoácidos , Proteínas Angiogênicas/química , Proteínas Angiogênicas/genética , Proteínas Angiogênicas/imunologia , Animais , Anticorpos Monoclonais/imunologia , Especificidade de Anticorpos , Reações Antígeno-Anticorpo , Encéfalo/citologia , Proteínas de Transporte/análise , Linhagem da Célula , Epitopos/imunologia , Proteínas do Olho/biossíntese , Proteínas do Olho/química , Proteínas do Olho/genética , Proteínas do Olho/imunologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Moleculares , Desenvolvimento Muscular , Proteína MyoD/análise , Especificidade de Órgãos , Conformação Proteica , Domínios Proteicos , Coelhos , Ratos Sprague-Dawley , Receptores Acoplados a Proteínas-G/química , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/imunologia , Sequências Repetitivas de Aminoácidos , Pele/citologia , Especificidade da Espécie , Tatuagem , Adulto Jovem
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